1. Field of the Invention
The present application is directed to therapeutic compositions including an osmotic agent and an active agent and, in particular, to compositions including dimethyl isosorbide as the osmotic agent.
2. Related Art
Cells and other membranous tissues contain and are surrounded by various fluids that contain electrolytes. The difference in the type and concentration of the electrolytes contained in the cells and membranous tissues may in some instances polarize, or provide an electrical potential across the membrane. For example, in general, the electrolytic fluid contained in the interior of a cell contains more negatively charged ions than the electrolytic fluid surrounding the exterior of the cells, which contains positively charged ions. Thus, it can be seen that the normal state of cells is one in which the electrical charge of the fluids contained in and surround a cell are not balanced. The normal charge difference across the membrane creates an electrical potential which is known as the resting threshold potential. For a nerve to conduct a pain impulse, it must be at its resting threshold potential.
With respect to nerve cells, the electrolytic fluid in the interior of a nerve cell at rest has a resting threshold potential of about xe2x88x9285 millivolts with respect to the electrolytic fluid surrounding the nerve cell. Pain is felt by a subject when an irritant to the nerve cell occurs, causing sodium channels in the nerve cell membrane to open for a brief period of time (on the order of milliseconds), allowing sodium ions contained in the fluid surrounding the nerve cells to move into the fluid contained in the interior of the nerve cells, after which conduction along the nerve takes place, leading to a complete action potential and pain emission.
One example of such a mechanism involves the pulpal nerves. The electrolytic fluid in the interior of the pulpal nerves has a resting threshold potential of about xe2x88x9285 millivolts with respect to the electrolytic fluid surrounding the pulpal nerve cell. When an irritant of about +15 millivolts occurs, sodium ions in the fluid surrounding the pulpal nerve move across the pulpal nerve membrane to the interior of the pulpal nerve and conduction takes place, leading to a complete action potential and pain emission.
One known mechanism for preventing pain in pulpal nerves is to increase the concentration of potassium ions in the electrolytic fluid surrounding the pulpal nerves. Surrounding the pulpal nerves with a high concentration of potassium ions causes the nerve to depolarize. xe2x80x9cDepolarizationxe2x80x9d occurs when the resting threshold potential is increased. In the present instance, the resting threshold potential is increased from xe2x88x9285 millivolts to zero or a positive value. When the resting threshold potential is zero, or a positive value, the nerve cannot initiate a pain impulse. Thus, it is known that if the resting threshold potential of a nerve is increased, it is possible to prevent an action potential from taking place, the nerve will be unable to conduct an impulse, and the subject will not feel pain.
In theory, pain inhibition in the pulpal nerves may be accomplished by a varoety of mechanisms. However, in practice, anatomical constrictions, irregularities, and other resistances ound in the dentinal tubles sometim potassium ions from reaching the electrolytic fluid surrounding the nerve cell.
Any mechanism for charging the resting threshold potential of nerves is desirable for interfering with its ability to illicit pain.
The present invention is directed, in one embodiment, to a method of decreasing the volume of a cell having a membrane and an electrical potential across the membrane that is substantially equal to a resting threshold potential. The method involves the steps of topically applying a composition containing an osmotic agent, increasing the electrical potential across the cell membrane to a level greater than the resting threshold potential, and decreasing the electrical potential across the cell membrane to a level less than the resting threshold potential.
In another embodiment, the invention is directed to a therapeutic composition. The therapeutic composition includes dimethyl isosorbide and an active agent.
Another embodiment of the present invention is directed to a method of treating a subject. The method involves topically applying an effective amount of a composition containing an osmotic agent and an active agent to an area to be treated.
Another embodiment of the present invention is directed to a method of treating a subject. The method involves topically applying an effective amount of a composition containing dimethyl isosorbide and an active agent to an area to be treated.
The present invention is directed to therapeutic compositions containing at least one osmotic agent and at least one active agent. The compositions may be used topically by subjects to treat, relieve, or treat and relieve, the symptoms of various conditions and disorders, by providing improved delivery of the active agent contained in the composition to the region of interest. The amount of the osmotic agent, the amount of the active agent, or the amount of both the osmotic agent and the active agent contained in the present compositions may be varied in order to achieve the desired therapeutic results. This may be easily accomplished by those of skill in the art using routine experimentation and traditional techniques.
In practice, anatomical constrictions, irregularities, and resistances may sometimes minimize or prevent active agents from reaching a targeted site selected for therapeutic treatment. xe2x80x9cOsmotic agent,xe2x80x9d as used herein, means any agent that raises the osmotic pressure of fluid on one side of a membranous structure drawing water across the membrane, causing the structure to shrink in volume. Using the example of a cell, an osmotic agent according to the present compositions may draw water from the interior of the cell such that the volume of the cell is reduced. When cells in a targeted region are reduced in volume, the intercellular spaces are increased. Thus, the osmotic agents of the present compositions increase the amount of space available between cells, allowing the electrolytic fluid surrounding the cells to move more freely and quickly between the cells.
In addition to increasing the intercellular volume, the reduction in cell volume resulting from the osmotic agents disturbs the normal function of the cells, i.e., the cell with reduced volume is unable to function normally. The functions of nerves that may be disturbed as a result of the cell volume reduction may include the ability to stimulate an inflammatory response and the ability to illicit pain, depending on whether the nerves are from the central nervous system or the autonomic nervous system.
The present compositions unexpectedly allow active agents to be delivered directly to deeper targeted sites, eliminating the need for injections, or systemic (oral) medications that may present safety concerns. The present compositions have the capability to readily penetrate into and through the skin, and in some instances into the underlying tissue. In this manner, the osmotic agent of the present compositions increases the absorption and penetration depth of the active agents into, for example, the skin and underlying tissues, the mucosae, and teeth. Thus, the therapeutic effectiveness of the active agent may be increased for its desired purpose. The increased therapeutic effectiveness of active agents in the present compositions, without untoward side effects, is unexpected.
As a result, many otherwise suitable active agents may be made therapeutically effective by the addition of an osmotic agent to a composition containing an active agent. For example, many active agents have been used to treat diseases or conditions unsuccessfully. In some instances, they have been unsuccessful because the delivery agent involves other tissues and systems (digestive, absorptive, vascular) that are not affected by the disease or conditions, which is generally undesirable. Thus, the active agents are made therapeutically effective with the addition of osmotic agent (tissue healing, pain elimination, etc.) because other systems are not involved and it targets the affected tissues, penetrating them directly.
It is thought that the beneficial effects and therapeutic effectiveness of many active agents are enhanced by the addition of the osmotic agent apparently without entering the deeper pharmokinetic pathways, such as the vascular system, the gastro-intestinal system, or the endocrine system. Therefore, treatment with the present compositions does not involve healthy tissue and eliminates the possibility of side effects, making each substance more effective as a disease fighter, without hazards and side effects.
Suitable osmotic agents that may be used in the present compositions include any agent that raises the osmotic pressure of fluid on one side of a membranous structure and draws water across the membrane, causing the structure giving up the water to shrink in volume. One preferred osmotic agent is dimethyl isosorbide (DMI). While not wishing to be bound to any theory, it is thought that the methyl groups of DMI make it more lipid soluble and increases its capability of being able to pass through membranes in comparison to isosorbide, allowing DMI to cross barriers such as skin or tissue membranes more easily and quickly, much like DMSO. DMI""s ability to penetrate barriers provides enhanced penetration and/or absorption of the active agents to the targeted treatment site. Thus, DMI acts as a delivery vehicle for active agents that might otherwise require injection, and this is accomplished without involving other tissues or systems.
The possibilities are enormous as differing beneficial agents for varying treatment regimes can be delivered into targeted sites attacking the problem directly. DMI by virtue of its osmotic penetrating synergizing quality opens a direct route of drug administration enabling targeted therapy that is non-invasive. It encourages patient compliance, and is well tolerated. xe2x80x9cActive agent,xe2x80x9d as used herein, means any beneficial substance including medications, minerals, potassium compounds, corticosteroid, antibiotics, antihistamines, anti-inflammatories, ansaids, nutrients, chemotherapeutic agents, vitamins, and combinations thereof.
Suitable active agents that may be responsive to the synergistic effect of osmotic agent include anti-inflammatories; dentifrices; desensitizing agents; pain relievers; anti-fungal agents; topical anesthetics, e.g: benzocaine, tetracaine, benadryl, etc.; moisturizers; humectants; anti-wrinkle or anti-aging preparations; skin pigment removers; skin cleansers (colds creams); skin peels (e.g. Alpha hydroxy, citric acids, ascorbic acid, retinyl palmitate); antibacterials, e.g.: chlorhexadine, etc., for oral rinses and dermatological usage. The may also be used to treat and prevent periodontal disease being brought by the osmotic into the gingival tissues; sun tanning and blocking preparations (e.g. PABA); sterilizing agents (e.g. alcohol); anti-itch preparations (calamine lotion); topical antibiotics (e.g. Bacitracin, Neosporin); nutrients; preparations that contain sunflower seed oil, nutrients and other agents (e.g. mucopolysaccharides, wheat protein, wheat amino acids, yeast extract, cysteine, methionine, glutamine, biotin, niacin, tocopherol, lineic acid, arochidoric acid, saw palmetto extract, methyl nicotinate, ginseng extract, inositol, tetrasodium EDTA); agents that improve hair health and growth; balms used to relive muscle pain (e.g. camphor, menthol, salicylate (menthol, trolanne), capsacin); and, pain relieving hemorrhoid preparations (e.g. Preparation-H), antihistamines, ansaids, chemotherapeutic agents, vitamins, corticosteroid, antibiotics, potassium compounds, minerals, and other beneficial substances.
Thus, the present compositions containing osmotic agent and an active agent have increased therapeutic effectiveness in comparison to compositions without the osmotic agent.
Increasing the concentration of the osmotic agent in the electrolytic fluid surrounding a cell increases the osmotic pressure of the electrolytic fluid surrounding the cell. An increase in the osmotic pressure in the electrolytic fluid surrounding the cell causes water to be drawn from the interior of the cell, resulting in a reduction in cell volume (cell shrinkage).
In order to regain equilibrium, the cell must restore its lost volume. Potassium ion influx is necessary to restore cell volume. Cell and membranous tissue shrinkage provides a strong stimulus for the uptake of potassium across the cell membrane, into the interior of the nerve cell, resulting in an increased concentration of potassium ions in the electrolytic fluid contained in the cell.
In order to regain equilibrium, the potassium ions contained in the electrolytic fluid contained in the interior of the cell will escape and cross the cell membrane into the electrolytic fluid surrounding the cell. When this occurs, the electrical potential across the cell membrane is increased, resulting in a potential that is more highly negative than the resting threshold potential, typically on the order of about xe2x88x92110 millivolts. Because a nerve cell must be at its resting threshold potential in order to form an action potential for the conduction of pain, the increased negative potential (hyperpolarity) across the cell membrane prevents this from occurring. Moreover, the potassium ions in the electrolytic fluid that surrounds the nerve cell slows the escape of potassium ions from the electrolytic fluid contained within the cell, further delaying the cell""s return to its normal volume and normal resting threshold potential (xe2x88x9285 mvs.) To conduct an impulse, the nerve must be at the normal resting threshold potential. Thus, the nerve cannot conduct an impulse.
The compositions described above are administered in effective amounts. An effective amount is a dosage of the composition sufficient to provide a medically desirably result. The effective amount will vary with the particular condition being treated, the age and physical condition of the subject being treated, the severity of the condition, the duration of the treatment, the nature of the concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. For example, an effective amount for treating psoriasis would be an amount sufficient to slow or halt the development or further progression of psoriatic lesions. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgment.
It is expected that the compositions may be applied in one or several administrations per day, preferably topically. In the event that a response in the subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.
When administered, the pharmaceutical preparations of the invention are applied in pharmaceutically-acceptable amounts and in pharmaceutically-acceptably compositions. Such preparations may routinely contain salt, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically-acceptable salts thereof and are not excluded from the scope of the invention. Such pharmacologically and pharmaceutically-acceptable salts include, but are not limited to, those prepared from the following acids: hydrocholoric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like. Also, pharmaceutically-acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.
The compositions may be combined, optionally, with a pharmaceutically-acceptable carrier. The term xe2x80x9cpharmaceutically-acceptable carrierxe2x80x9d as used herein means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration into a human or other animal. The term xe2x80x9ccarrierxe2x80x9d denotes an organic or inorganic ingredient, natural or synthetic, with which the active agent is combined to facilitate the application. The components of the osmotic agents and the active agents also are capable of being co-mingled with such carriers, other additives, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.
The pharmaceutical compositions may contain suitable buffering agents, including: acetic acid in a salt; citric acid in a salt; boric acid in a salt; and phosphoric acid in a salt. The pharmaceutical compositions also may contain, optionally, suitable preservatives, such as: benzalkonium chloride; chlorobutanol; parabens and thimerosal. The compositions may also include a variety of other materials such as solvents, surfactants, thickeners, colorants, flavorants, and the like.
A variety of administration routes are available. The particular mode selected will depend of course, upon the particular active agent selected, the severity of the condition being treated and the dosage required for therapeutic efficacy. The methods of the invention, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active agents without causing clinically unacceptable adverse effects. According to one particular characteristic of the invention, these products are used for the preparation of a pharmaceutical composition intended for local topical application, and may be in any suitable form including liquids, pastes, creams, ointments, gels, lotions, chewing gum, or any other form desired. The pharmaceutical composition may also be in the form of a liquid, soft capsules, solution, or transdermal patches containing the active agent. Such modes of administration include topical routes.
The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods may include the step of bringing the active agents and osmotic agents into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions may be prepared by uniformly and intimately bringing the active agents into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
Compositions suitable for oral administration may be presented as discrete units, such as capsules, tablets, lozenges, each containing a predetermined amount of the active agents. Other compositions include suspensions in aqueous liquids or non-aqueous liquids such as a syrup, elixir or an emulsion.
Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the active agents described above, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer base systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Pat. No. 5,075,109. Delivery systems also include non-polymer systems that are: lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-di- and tri-glycerides; hydrogel release systems; sylastic systems; peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like.
Use of a long-term sustained release implant may be particularly suitable for treatment of chronic conditions. Long-term release, are used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active agent for at least 30 days, and preferably 60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.
In some embodiments of the present composition, the active agent may be a pain reliever or desensitizer. xe2x80x9cPain reliever,xe2x80x9d as used herein, means an active agent that reduces or eliminates a subject""s pain. xe2x80x9cDesensitizer,xe2x80x9d as used herein, means an active agent that reduces or eliminates a subject""s sensitivity to a sensitizing agent or to a sensitive area of the subject""s body. One preferred composition includes potassium ions, from potassium nitrate, as a pain reliever and/or a desensitizer. Potassium ions from a potassium nitrate source are known to desensitize hypersensitive teeth by nerve depolarization. Potassium nitrate travels through the dentinal tubules and causes the pulpal nerves to depolarize by bathing them with potassium ions. The relatively high concentration of potassium ions contained in the electrolytic fluid surrounding the pulpal nerves changes the resting threshold potential of the pulpal nerve from xe2x88x9285 millivolts to zero or a positive value and prevents initiation of an action potential. This inhibits nerve conductance and pain emission, and in this way it desensitizes hypersensitive teeth.
A composition containing an osmotic agent and potassium nitrate is able to reduce the cell volume, increase the intercellular openings and increase the amount of potassium ions that may be delivered to the pulpal nerve in comparison to a composition without the osmotic agent.
The increased intercellular volume resulting from the osmotic agent allows the composition including potassium nitrate to overcome the resistant factors of the dentin/pulp barriers and to more rapidly reach the pulpal nerves, blood vessels, and embryonic connection tissues. It overcomes the tubular constrictions, irregularities, man-made tubular obliterations, dentinal sclerosis, odontoblast processes, fluid with contained minerals and immunoglobulins, tubule contained bacteria, antibiotics, anti-microbial agents, odontoblasts, odontoblast junctions (tight, intermediate, and gap), and intercellular bridges that restrict and slow the penetration of potassium ions into pulpal tissues. As the osmotic agent advances through the dentinal tubules, it encounters the previously mentioned structures. Due to its osmotic qualities, the osmotic agent opens intercellular spaces between cells as well as spaces through cells. The intercellular bridges connecting cells (odontoblasts) serve as permeability barriers.
The present compositions can then flow through the bridge spaces, junctions, and enlarged openings between the shrunken odontoblasts processes and odontoblasts, enhancing the permeability of the dentin/pulp. The fluid containing the potassium ions then flows more rapidly and easily through the newly created spaces to reach the pulpal nerves and blood vessels.
In a similar manner, pulpal nerves lose water and shrink significantly due to the increased osmotic pressure caused by the surrounding fluid containing potassium nitrate and osmotic agent. When cells and membranous structures are caused to shrink osmotically, potassium located outside the nerves"" membrane, as well as potassium from the high potassium gradient obtained from the potassium nitrate desensitizer, flows into these nerve cells in quantity. Osmotic cell shrinkage is a strong stimulus for the uptake of potassium. As the captured potassium leaves the inside of nerves, it escapes, leaving a strongly negative hyperpolarized nerve that cannot form an action potential. This dynamic process inhibits pain production and conduction.
Thus, desensitization of hypersensitive teeth may be accomplished by simultaneously depolarizing and hyperpolarizing the pulpal nerves. The osmotic agent DMI works with KNO3 to disturb the functions of the nerve cell simultaneously depolarizing and hyperpolarizing it. These agents antagonize the recovery process to the resting potential. Potassium positioned on the outside of the nerve keeps it depolarized. This slows the escape of the potassium held between the nerve""s membranes and makes it more difficult for the nerve to recover volume after shrinking. A lot of potassium outside the nerve keeps the cell shrunken and the nerve so shrunken, is not going to work well. This keeps the nerves inactive longer and causes a faster, more complete, and longer lasting desensitization to take place than potassium nitrate alone that bathes the outside of the pulpal nerves only.
An application of potassium nitrate/osmotic agent desensitizer continues to desensitize for hours after its initial application because the composition accomplishes desensitization without obliterating or diminishing the radii of the dentinal tubules. The dentin/pulp circulation and mineral defense system remains functionally intact, flowing, and even improved, which is important for the long term health and longevity of the dentition. It may be helped by the nitrate ion, since nitrate salts tend to increase circulation by being converted to nitric oxide. This is very important for long term vitality and longevity of the dentition as the dentin/pulp""s afferent/efferent circulatory system is an extension of the pulp and its long term health is dependent on its remaining functional and flowing. It serves to replenish the dentin""s mineral loss and as a barrier to combat the penetration of noxious substances and bacteria as well as a warning system for untoward changes that could make the pulp unhealthy. It may help also to accommodate for barometric and atmospheric changes such as is seen with deep sea diving, or air and space travel.
It takes usually 2-4 weeks for the potassium ions to penetrate through the structures described above, and into the pulp surrounding the nerves in sufficient numbers to desensitize a hypersensitive tooth. The addition of osmotic agent to compositions containing potassium increases the flow of potassium ions, nitrate ions, and fluoride through the dentin, quickly reaching the pulp in sufficient quantities to effect more complete, more rapid, and more lasting desensitization of supersensitive teeth.
Suitable potassium containing compounds include potassium bicarbonate, potassium biphthalate, potassium bromide, potassium chromate, potassium dichromate, potassium sulfate, potassium chromium sulfate, potassium thiocyanate, potassium bitartrate, potassium alum, potassium bromate, potassium fluoride, potassium hydrogen sulfate, potassium iodate, potassium tartrate, and other potassium compounds. Preferred potassium sources include potassium nitrate, potassium acetate, potassium chloride, potassium citrate, potassium phosphate, potassium carbonate, and other potassium compounds. Potassium nitrate is especially preferred because it can penetrate membranes readily, the nitrate yields nitric oxide, a blood vessel dilator, and it clinically works well to desensitize teeth.
Potassium is also known to be useful to treat ulcerative lesions of an oral and dermatologic nature. The present compositions containing potassium have been found to reduce or eliminate the pain associated with ulcers, especially aphthous ulcers, as well as herpes and Herpes Labialis. Some of the oral ulcerative lesions are acute necrotizing ulcerative gingivitis (ANUG), bullous ulcers, aphthous and herpetic lesions, traumatic ulcers, pemphigus, AIDS related ulcers, bullous Lichen Planus, oral shingles and others. Many of these ulcers are oral manifestations of dermatologic illnesses. Aphthous (Behcets), traumatic ulcers, Lichen Planus, Pemphigus, Lupus, are some of these diseases. Another of these ulcerative oral ulcers are seen as a sequelae to chemotherapy and radiation therapy. Shingles often exhibits dermatologic ulcers.
In both labial herpes and shingles the potassium ion if it was to help this condition would have to penetrate the skin and surround the involved nerve thus changing the nerve""s threshold potential from about xe2x88x9280 to xe2x88x9290 millivolts to a zero or positive value. Potassium gels without dimethyl isosorbide are moderately helpful. A potassium nitrate gel with DMI increases the amount and speed of penetration of the ionic potassium. A high gradient of potassium is able to surround the nerves (central nervous system nerves and automatic system nerves) changing the threshold potential and preventing an action potential from taking place, and initiating pain or/and failing to allow the automatic nerves to signal for an inflammatory response. This makes the nerve unable to conduct an impulse thus eliminating the pain of these disease entities and hastening healing. For the treatment of ulcers, viscous preparations such as creams or gels are preferable because when applied liberally to the ulcers, they remain on the lesions and continually feed potassium into them, which reduces pain and hastens healing by reducing the inflammatory response. Suitable potassium containing compounds include those previously mentioned.
In one embodiment of the present composition, the active agent may be a topical corticosteroid. Topical corticosteroids may be absorbed from normal intact skin. When combined with DMI, the absorption of topical corticosteroids by the lesion is improved. As topical corticosteroids are absorbed through the skin, they enter pharmokinetic pathways similar to systemically administered corticosteroids. Topical corticosteroids are generally used for the treatment of swelling, inflammation, itching, and combinations thereof. Thus, topical corticosteroids are effective in the treatment of corticosteroid-responsive dermatoses primarily because of the anti-inflammatory, antipruritic and vasoconstrictive actions. Such symptoms may be caused by any number of skin conditions including eczema, dermatitis, rashes, insect bites, poison ivy, poison sumac, soaps, detergents, cosmetics, jewelry, Seborrheic Dermatitis, psoriasis, external anal and genital itching.
The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the delivery vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Inflammation and/or other disease processes in the skin may increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Examples of topical corticosteroids include betamethasone, clobetasol, diisopropionate, dipropionate, hydrocortisone, propionate, and combinations thereof.
A preferred composition includes the topical corticosteroid betamethasone an active agent. The composition may be effective for treating, among other things, psoriasis, as betamethasone is often used to reduce inflammation of the skin of subjects with psoriasis. Psoriasis may be characterized by increased cell proliferation and increased skin thickening. The skin of subjects with psoriasis acts as a barrier to the absorption of corticosteroids and even percutaneous absorptive medications do not have the ability to fully penetrate to and below the basal membranes to reduce or arrest the proliferation and skin thickening seen in conditions such as psoriasis. The addition of osmotic agent to corticosteroids (or vitamin D) used to treat psoriasis enhances the absorption amount and penetration depth of the corticosteroid into the very proliferative skin layers of the psoriatic skin lesions, increasing the anti-inflammatory effect of the corticosteroid.
In another embodiment of the present composition, the active agent may be an anti-inflammatory drug. The osmotic agent enhances the passage of various molecules through the skin to the underlying tissues. One preferred embodiment of a composition includes the non-steroidal anti-inflammatory drug (NSAID), and vioxx, and the like which is an effective oral therapy for pain and inflammatory conditions. Such topical compositions, vioxx, and others may provide distinct advantages compared to oral usage. Thus, arthritis and other painful, inflammatory conditions may be treated while eliminating many of the safety issues associated with the oral use.
In another embodiment of the present composition, the active agent may be an anti-viral substances such as acetosalicylic acid, which is commonly used for the removal of warts. Osmotic agent increases the penetration and absorption of the acetosalicylic acid into and through the wart(s) thickness increasing the effectiveness of the active agent. The composition improves the penetration of the acetosalicylic acid into the basal layers of the wart to achieve increased effectiveness and efficacy of the active agent. Thus, healing of the wart lesions take place more quickly and completely than the preparation containing only acetosalicylic acid as an active agent. The composition may be effective for the treatment of all types of warts.
Other embodiments of the present composition may include anti-fungal substances such as amorolfine, ciclopirox, oxiconazole, and nystatin which are typically used to treat fungal infections of the nail (onychomycoses), which can occur in, around, or under the nail plate. Such infections are common and are reported in 2% to 14% of the population, but the actual incidence is probably much higher. The microorganisms involved are usually molds such as trichophyton rubrum, or yeasts, such as candida. Clinical investigations have demonstrated that it is feasible to treat fungal infections of the nail through the topical delivery of these antifungal agents. However, onset of visible cure is slow, treatment is usually long-term, and re-infection often occurs. The lack of a rapid visible onset of cure is a major reason for lack of patient compliance during therapy. By combining such substances with osmotic agent, the rate and extent of delivery of the aforementioned active agents through the nail plate to the nail bed is increased. Thus, therapeutically effective levels of the antifungal active agent within and below the nail are rapidly achieved, increasing the onset of the visible cure of fungal infections of nails.
In another embodiment of the composition the active agent may be a caries fighting substance. Most commercial dentifrices contain at least one caries fighting substance. xe2x80x9cDentifrice,xe2x80x9d as used herein, means a powder, paste, gel, or liquid for cleaning the teeth. Osmotic agent increases the penetration of caries fighting substances into tooth matter (enamel and dentin). For example, osmotic agent enhances the penetration of the fluoride ion into the tooth enamel and the 30,000-59,000/mm2 dentinal tubules by with brushing with a dentifrice that contains fluoride and osmotic agent. The resistance of enamel and dentin to fluoride penetration is overcome and the fluoride ions penetrate in larger quantities and penetrate the tubular system in greater numbers enhancing the ability of fluoride to be a caries (including root caries) fighter. This is of major importance as fluoride is a major element involved in caries prevention, and when its effectiveness is enhanced and improved the battle against caries becomes more successful.
Suitable sources of fluoride include stannous fluoride, sodium fluoride, sodium monofluorophosphate, potassium fluoride, and the like. However, any source of fluoride may be used, as they all result in the release of fluoride ions into the saliva.
Potassium from any of the previously mentioned sources and fluoride from any of the previously mentioned sources may be incorporated into chewing gums and chewed to supply potassium ions for desensitizing/anesthetizing, as disclosed in U.S. patent application Ser. No. 5,522,726, to treat ulcers, and to fight caries with fluoride ions to the saliva and into tooth structure. Osmotic agent may also be combined with the chewing gums to enhance the penetration of such substances into the ulcers and tooth enamel and dentin (dentinal tubules), resulting in improved desensitization, protection from caries, or both. Upon being chewed, such a chewing gum releases the desensitizers directly into the saliva, allowing the active agents to enter the ulcers and the dentinal tubules and pass into the pulp. Such chewing gums also release the caries fighting substances directly into the saliva and then into tooth structure to prevent tooth decay. This effectively increases the desensitizing effect of potassium and allows the method of these ingredients being incorporated into chewing gum to be very effective for fighting caries and treating dentinal hypersensitivity (pain from thermal (hot, cold) chemical (sweet, sour, salt, acid etc.), and tactile (touch, brushing).
In another embodiment, the active agent may be a formulation for the treatment of erectile dysfunction, such as alprostadil. In the present embodiment, the composition is preferably formulated as a cream or ointment, and is applied locally on the glans (the head) of the penis. Thus, the side effects of delivery by injection or orally (e.g. with Viagra), such as heart attacks, possibly hitting a blood vessel during injection, and hematoma may be avoided. This approach to the treatment of impotence has important advantages.